The G protein-coupled bile acid receptor (GPBAR1) is a possible new drug target for the treatment of metabolic and inflammatory diseases, including type 2 diabetes. Previously, it has been shown that a number of herbal remedies and natural small molecule metabolites were able to activate this receptor and thus may exert antidiabetic and anti-inflammatory effects. The fast-forward identification of GPBAR1 agonists is highly relevant, as metabolic diseases like type 2 diabetes have become an epidemic, and novel treatments are urgently needed [1].
The aim of this study was to generate reliable prediction models for the fast-forward assessment of GPBAR1 activating natural compounds. A cheminformatics workflow including ligand-based pharmacophore- and shape-based virtual screening was set up. The workflow was validated theoretically and employed for the prospective virtual screening of open-source and in-house molecular databases. From 34 chemically diverse virtual hits subjected to experimental testing, 14 were confirmed as GPBAR1 activators, including new scaffolds from natural and synthetic origin. Triterpenes previously isolated from the South African tree Burkea africana [2] and coumarins from the middle-eastern spice Ferula assa-foetida [3] showed activities comparable to the endogenous ligands chenodeoxycholic acid and lithocholic acid.
[1] Ladurner A, Zehl M, Grienke U, Hofstadler C, Faur N, Pereira FC, Berry D, Dirsch VM, Rollinger JM. Front Pharmacol 2017; 8: 468
[2] Mair CE, Grienke U, Wilhelm A, Urban E, Zehl M, Schmidtke M, Rollinger JM. J Nat Prod 2018; 81(3): 515-523
[3] Rollinger JM, Steindl TM, Schuster D, Kirchmair J, Anrain K, Ellmerer EP, Langer T, Stuppner H, Wutzler P, Schmidtke M. J Med Chem. 2008 Feb 28;51(4):842-51